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A ANSF 2008 A review on treatment of Alzheimer’s disease

Suman Pratihar*, Shomik Nag and Jayanta Kumar Kundu Molecular Biology Unit, Department of Zoology, Vidyasagar University, Midnapore (W.B), INDIA *Corresponding author. E-mail: [email protected]

Abstract: Alzheimer’s disease is a brain disorder named after German physician Alois Alzheimer, who first described it in 1906. The Alzheimer’s disease is now becoming curable by identifying the actual cause of the disease with the proper diagnosis of the disease of the patient. The disease can now be cured by drug treatment, by hormonal treatment and by using herbal products such as medicines. The drugs are based on antagonizing action of the components against the causative agents (â Amyloid plaque, Apolipoprotein E, Tau protein) of the disease. The common drugs based on their action are N-methyl-D-aspartate (NMDA) receptor antagonists, Cholinesterase inhibitor, agents for increasing blood supply and neurotransmitter in the brain, lipofuchsin and â Amyloid plaque inhibitor, free radical scavenger, agent for metal chelator and agent for increasing macrophage activity in the brain. Keywords: Alzheimer’s disease, Memantine, Hydergine, Rivastigmine tartrate, Turmeric

INTRODUCTION to form clumps similar to the plaques of Alzheimer’s Alzheimer’s disease (AD) also called Alzheimer disease, disease. Senile Dementia of the Alzheimer Type (SDAT) or simply The plaques, often known as â amyloid plaques are focal, Alzheimer’s is the most common form of dementia where spherical, collections of dilated, tortuous, silver staining, dementia (from Latin de- “apart, away” + mens “mind”) is neuritic process (dystrophic neurites) often around a the progressive decline in cognitive function due to central amyloid core, which may be surrounded by clear damage or disease in the body beyond what might be halo. Plaques can be found in the hippocampus and expected from normal aging. Generally it is diagnosed in amygdale as well as in the neocortex. The amyloid core people over 65 years of age, although the less-prevalent which can be stained by Congo red, contains several early-onset Alzheimer’s can occur much earlier. An abnormal proteins (like as Amyloid Precursor protein, estimated 26.6 million people worldwide had Alzheimer’s Apolipoprotein E and Tau Protein). However, in 2006; this number may quadruple by 2050 (Brookmeyer Neurofibrillary tangles are bundles of filaments in the et al., 2007). This degenerative and terminal disease was cytoplasm of the neurons that displace or encircle the first described by German psychiatrist Alois Alzheimer nucleus They are commonly found in cortical neurons, in 1906 by observing the patient Auguste D. especially in the entorhinal cortex, as well as in other in Modern research indicates that the disease is associated other sites such as in other sites such as pyramidal cells, with plaques and tangles in the brain (Tiraboschi et al., as well as in pyramidal cells of the hippocampus, the 2004).Brain atrophy reveal the damage caused by amygdala, the basal forebrain and the raphe nuclei. In Alzheimer’s disease. Certain regions of the brains- pyramidal neurons, they often have an elongated “flame” including the hippocampus and cortex – lose functions shape; in rounder cells, the basket wave of fibers around and the normally convoluted surface of the brain the nucleus take on a rounded contour. They are visible ultimately wastes away. Various studies have found that in silver staining. groups of people exposed to high levels of aluminum do CAUSES OF ALZHEIMER’S DISEASE not have an increased risk. Moreover, aluminum in cooking utensils does not get into food and the aluminum According to Amyloid hypothesis, following factors are that does occur naturally in some foods, such as potatoes, responsible for Alzheimer’s disease: is not absorbed well by the body. On the whole, scientists A. Role of amyloid precursor protein in alzheimer’s can say only that it is still uncertain and rather unlikely disease: Amyloid Precursor Protein (APP) is a 695-770 that exposure to aluminum plays a role in Alzheimer’s amino acid long transmembrane protein. The gene for disease. On the other hand, a recent study suggests that this protein is situated on chromosome 21.It has cleavage too much zinc might be the problem. In an experiment, site for three enzymes which are- â secretase, á secretase zinc caused soluble beta amyloid from cerebrospinal fluid and ã- secretase. Normally âAPP is cut twice, first by â

ISSN : 0974-9411 All Rights Reserved © Applied and Natural Science Foundation www.ansfoundation.org 160 Suman Pratihar et al. /J. Appl. & Nat. Sci. 2 (1): 159-164 (2010) secretase to C99-âAPP, then by ã secretase to either 40 â the characteristics of the disease (among other things amyloid protein (normally 90% produced) or 42 â amyloid neurofibrillary tangles and neuritic plaques) of all protein (normally 10% produced). Mutation in âAPP gene Alzheimer patients two of these ‘+1 proteins’, i.e. found and believed to produce a form of the protein with ubiquitin B+1 and amyloid precursor protein+1 (UBB+1 shifted amino acids which guide â secretase followed by and APP+1) have been found. Meanwhile the researchers ã secretase to cut the protein preferentially into 42 â have demonstrated that UBB+1 inhibit the action of the amyloid protein which can aggregates and form fibrils. proteasome. The proteasome is involved in the enzymatic As APP is encoded from chromosome 21, thus peoples decomposition of many (aberrating) proteins. A not well with Down’s syndrome have an increased risk of functioning ubiquitin-proteasome system may be one of developing familial Alzheimer’s disease. (Lott and Head, the causes that eventually nerve cells become less active 2005). and even die. UBB+1 is an important chain in the B. Role of apo lipoprotein E in alzheimer’s disease: Apo neurotoxicity of the beta-amyloid protein (present in lipoprotein E is coded by the gene APOE on chromosome plaques) (Leeuwan, 2001). 19 and it comes in three forms -å2, å3, å4. It plays many SYMPTOMS OF ALZHEIMER’S DISEASE important roles in body like as- transports cholesterol in Following are the different stages of Alzheimer’s disease body, helps in cellular repair and regeneration. Amyloid with symptoms: proteins are transported into the cell by membrane bound Predementa: The most noticeable deficit is memory loss, protein transporters. In AD there appears to be an which shows up as difficulty in remembering recently interface with transport of 42 âamyloid protein by APOE learned facts and inability to acquire new information. (Apolipoprotein å4 form). Toxic â amyloid fragments (Arnáiz and Almkvist., 2003) Subtle problems with the builds up outside the cell. Sometimes the å4 form of executive functions of attentiveness, planning, flexibility, Apolipoprotein (APOE) is selectively removed from and abstract thinking, or impairments in semantic memory, extracellular space instead of the âamyloid-leaving the can also be symptomatic of the early stages of AD. latter to cause mischief. Apathy can be observed at this stage. C. Role of tau protein in alzheimer’s disease: Tau Early dementia: In this stage difficulties with language, proteins interact with tubulin to stabilize microtubules executive functions, perception (agnosia), or execution and promote tubulin assembly into microtubules. Tau of movements (apraxia) are more prominent than memory controlls microtubule stability by phosphorylation which problems (Forstl and Kurz, 1999). Language problems is regulated by a host of kinases. Hyperphosphorylation are mainly characterized by a shrinking vocabulary and of the tau protein (tau inclusions), can result in the self- decreased word fluency. While performing fine motor assembly of tangles of paired helical filaments and tasks such as writing, drawing or dressing, certain straight filaments, forming “Neuro fibrillary tangles” movement coordination and planning difficulties (apraxia) (Hernández and Avila, 2007). may be present, making sufferers appear clumsy (Benke, PROTEOMICS OF ALZHEIMER’S DISEASE 1993). Dr. van Leeuwan by discovering a new type of mutation Moderate dementia: During this phase complex motor suggested that due to molecular reading errors, sequences become less coordinated, reducing the ability transcripts (mRNA) may arise in which two nucleotide to perform most normal daily living activities, memory are missing. If these transcripts are translated in the +1 problems worsen, and the person may fail to recognize reading frame and the proteins do not decompose, they close relatives. Common neuropsychiatric manifestations may accumulate. Indeed this appeared to be the case: in are wandering, sun downing, irritability and labile affect, leading to crying, outbursts of unpremeditated Table 1. Genetics of alzheimer’s disease. Chromosome Gene Mutations/Alleles Consequences

21 Amyloid Precursor Protein 1) Single missense mutations 1)Early-onset AD 2) Double missense mutations 2)Increased A β production 3) Trisomy 21(gene dosage effect) 14 Presenilin (PS1) 1) Missense mutations 1) Early-onset AD 2) Splice site mutations 2) Increased A β production

1 Presenilin(PS2) Missense mutations 1) Early-onset FAD 2) Increased A β production 19 Apolipoprotein E(Apo E) Allele ε4 1) Increased risk of development of AD 2) Decreased age at onset of AD Suman Pratihar et al. /J. Appl. & Nat. Sci. 2 (1): 159-164 (2010) 161 aggression, or resistance to care giving. Adavanced dementia: In this stage, patients will ultimately not be able to perform even the simplest tasks without assistance. Muscle mass and mobility deteriorate to the point where they are bedridden, and they lose the ability to feed themselves. Finally comes death, usually caused directly pressure ulcers or pneumonia etc. DIAGNOSIS OF ALZHEIMER’S DISEASE Detecing alzheimer’s by eye test: The amyloid beta proteins which are a hallmark of Alzheimer’s are also found Fig. 1. Chemical structure of Memantine. in the lens and fluid of the eye. These proteins produce an unusual type of cataract in a different part of the eye. of the relevant signal such as in learning. Memantine is Scientists can detect these proteins by injecting a light- able to serve as a filter blocking ‘synaptic noise’ and sensitive dye, then shining a laser onto the specific part thereby allowing detection of the relevant signal i.e. of the lens where the cataracts tend to form. The synaptic plasticity is restored. (Danysz and Parsons, 2003) molecules in the dye bind to the protein molecules, if Side effects: The side effects of using Memantine as they are present, and the light will cause the resulting drug for Alzheimer’s disease are as follows: molecules to glow. This technique is called quasi-elastic I.Common symptoms: Dizziness, constipation, light scattering. hypertension, headache, somnolence etc. Detecting alzheimer’s by positron emission tomography II.Uncommon symptoms: Gait, Vomiting, scan: In this technique patients are injected with a thromboembolism, fatigue, hallucinations, confusion. radioactive dye called Pittsburgh Compound-B-or PIB. B. Ergoloid mesylates :Ergoloid mesylates is a mixture of Once it reaches the brain, PIB attaches to plaque. Then, the methanesulfonate salts of three dihydrogenated ergot a PET scan reveals areas with the most plaque build-up. alkaloids (dihydroergocristine, dihydroergocornine, and The pattern of PIB retention in the brain suggests that alpha- and beta-dihydroergocryptine). It is now present amyloid plaques formed by Alzheimer’s appearing first in market in different brand names like-Hydergine, in the frontal cortex areas, then progressing to the parietal Hydergina, Gerimal, Niloric, Redizork, Alkergot, Cicanol, and temporal cortex before ravaging the occipital and Redergin etc. The most important among them is sensory-motor cortex. (Kemppainen et al., 2008) Hydragine. Other techniques like-EEG Test, MRI Scan etc. are also Mechanism of action of Hydragine: used for diagnosis of the disease. I. Hydergine increase blood supply to the brain. II. Hydergine slows the deposit of the age pigment TREATMENTS OF ALZHEIMER’S DISEASE lipofuscin in the brain. There are some drugs which are now proven to be III. It Increase oxygen delivered to the brain and protects effective for the treatment of Alzheimer’s disease. They the brain from insufficient oxygen supply and also are like as Memantine, Hydergine, Exelon, Ginkgo biloba prevents free radical damage to brain cells (Spiegel, 1983). extracts (Oyama et al., 1996) etc. Beside these, different IV. Hydergine has also been shown to increase the level natural products such as Turmeric (Fiala et al., 2007) and of neurotransmitters in the brain, hormonal treatments are also useful. V. Hydergine enhances the metabolism of brain cells. A. Memantine:Memantine is the first representative of a There is also evidence that hydergine stimulates the moderate affinity NMDA receptor antagonist. NMDA growth of dendrite nerve fibers which is normally be receptor is a type of ionotropic receptor which is present expected to decline with aging. in brain and plays an important role in mediating plastic VI. In experiments it has been found that in young adult changes in brain .It has following features – rats, the energy required at synaptic regions are provided I. It is highly permeable to Ca2+ ions. by a large number of small, highly efficient mitochondria, II. It has voltage dependant blockage by Mg2+ ions. whereas in old rats, energy is produced by a smaller III. It shows slow gating kinetics. number of larger, less efficient mitochondria. But, after Mode of action: Under normal conditions, learning is treatment with Hydergine, it can be seen that the total based on detection of sufficiently strong signal over mitochondrial volume of old rats was nearly the same as baseline activity i.e. sufficient signal-to-noise ratio. the young rats. Furthermore, the mitochondrial size was Signal-to-noise ratio hypothesis assumes that in altered to a more youthful direction Alzheimer’s disease, due to overactive glutamatergic VII. Hydergine has also shown itself to be a mild system, Mg2+ is not effective enough to play its ‘filtering’ vasodilator (it enhances brain blood flow) and improves function. In turn, synaptic noise rises, impairing detection the uptake of the brain energy molecule – glucose. 162 Suman Pratihar et al. /J. Appl. & Nat. Sci. 2 (1): 159-164 (2010)

Hydergine also reduces the accumulation of age-related improve the symptoms of dementia (Oyama et al., 1996). toxin, lipofuscin. Mechanism of action of Ginkgo biloba: The mechanism Side effects: Hydergine has proven itself to be non-toxic of action of ginkgo is believed to be produced by its and relatively safe although its potential side effects functions as a neuroprotective agent, an antioxidant, a include mild nausea, gastric disturbances and bradycardia free-radical scavenger, a membrane stabilizer, and an and stomach upset. inhibitor of platelet-activating factor via the terpene C. Exelon (Rivastigmine tartrate): Exelon (rivastigmine ginkgolide B. The different components of Ginkgo biloba tartrate) is a cholinesterase inhibitor. Exelon is specifically like as Flavonoids contributes to its antioxidant property indicated for the treatment of mild to moderate dementia & Bilobalides helps to protects nerve cells and of the Alzheimer’s type and for the treatment of mild to regenerates nerve cells. Other pharmacologic effects moderate dementia associated with Alzheimer’s disease. include the following: endothelium relaxation mediated Mode of action of exelon: Based on their structure and by inhibition of 3’, 5’-cyclic GMP (guanosine mode of enzyme inhibition, ChEIs can be grouped into monophosphate) phosphodiesterase, inhibition of age- three classes: tertiary and quaternary amines, carbamates, related loss of muscarinergic cholinoceptors and and organophosphates. Acetyl cholinesterase (AChE), adrenoceptors; and stimulation of choline uptake in the the enzyme that breaks down ACh, is well characterized. hippocampus. Ginkgo extract also has been shown to It has two structural binding sites for ACh, an anionic inhibit beta-amyloid deposition. Some scientist site and an esteratic site, in two- and three-dimensional hypothesized that Ginkgo biloba treatment would have configurations. The ChEIs are classified according to their beneficial effects on cells exposed to the free radical duration of enzyme inhibition as short-acting, hydrogen peroxide (Oyama et al., 1996). intermediate-acting, or long-acting inhibitors. In contrast E. Turmeric:Turmeric is best known as one of the to Exelon, Tacrine and donepezil are short-acting ChEI ingredients used to make curry, it also gives ballpark that bind to AChE by hydrogen bonding and are mustard its bright yellow color. The turmeric plant hydrolyzed within minutes by the body’s water. Both (Curcuma longa or Curcuma domestica) is a member of rivastigmine and tacrine bind to AChE, however, the ginger family. It has aromatic, somewhat fleshy rivastigmine fits into the enzyme’s active site in a similar rhizomes that, when dried, yield a bright yellow powder fashion to ACh, which results in a “flattening” of the commonly used as a spice or coloring agent - sometimes carbamate moiety over the esteratic site, producing the both, as in certain yellow mustards. prolonged inhibition of AChE. In herbal medicine, turmeric (in the form of an extract of Like tacrine and donepezil, rivastigmine is hydrolyzed, Curcuma longa) is known for its action as: Anti- but unlike these two agents, it leaves the esteratic site hapatotoxic, Anti-hyperlipidemic, Anti-inflammatory, carbamylated and the phenolic derivative is excreted Antitumoral, Antimicrobial, Antifertile and mainly for its rapidly from the body. Sequestration of AChE in the antioxidant property. carbamylated form precludes further enzyme hydrolysis Role of turmeric preventing alzheimer’s disease: of ACh. On administration of a single dose, the carbamate I.Curcumin is a polyphenolic diketone from turmeric. moiety can inhibit enzyme activity up to10 hours. Due to Because of its anti-oxidant and anti-inflammatory effects, this longer duration of action, rivastigmine is classified it can reduce levels of amyloid and oxidized proteins and as an intermediate-acting (pseudo-irreversible) agent. can prevent cognitive deficits. It can also reduce amyloid Side effects :Adverse events associated with the use of aggregation by metal chelation. Metals can induce Aâ Exelon patch may include nausea, vomiting, diarrhea, aggregation and toxicity, and are concentrated in AD depression, headache, anxiety, anorexia, weight loss etc. brain. Using spectrophotometry, curcumin’s affinity for D. Ginkgo biloba:Ginkgo biloba is a type of tree that copper, zinc, and iron ions has been quantified. has existed for over 200 million years. The extract of dried Zn2+showed little binding, but each Cu2+ or Fe2+ ion leaves of this tree has been shown to have protective appeared to bind at least two curcumin molecules. Since effects against mitochondrial damage and oxidative curcumin more readily binds the redox-active metals iron stress. There are different variants of Ginkgo biloba and copper than redox-inactive zinc, curcumin might exert extracts available on the market today. Among them are a net protective effect against Aâ toxicity or might EGb 761, LI 1379, and Chinese Ginkgo extract ZGE. Ginkgo suppress inflammatory damage by preventing metal biloba is commonly used in the treatment of early-stage induction of NF-êB. Alzheimer’s disease, vascular dementia, peripheral II. Curcumin may interrupt the production of IL-2, a protein claudication, and tinnitus of vascular origin. Multiple that can play a key role in the destruction of myelin, the trials investigating the efficacy of ginkgo for treating sheath that serves to protect most nerves in the body. cerebrovascular disease and dementia have been III. Different studies have suggested that curcumin turns performed, and systematic reviews suggest the herb can on a gene that code for the production of antioxidant Suman Pratihar et al. /J. Appl. & Nat. Sci. 2 (1): 159-164 (2010) 163 proteins. A study showed curcumin’s role in the induction of the skill. Instead of remembering the skill for a few of the the heme oxygenase pathway, that produces the minutes as usual, they remembered it for weeks. potent antioxidant bilirubin, which protects the brain Drug for renal disorder cures alzheimers’s disease: against oxidative injury. Such oxidation is thought to be The research project showed that the drug sodium a major factor in Alzheimer’s disease. (Calabrese et al., phenyl butyrate, prescribed until now for patients with 2003) Another study confirmed that, curcumin strongly alterations in the urea cycle, eases the fusion of proteins induces expression of hemeoxygenase-1 (HO-1) gene in responsible for neuron connections, thus increasing the astrocytes from the hippocampal region of the brain. learning capacity of the mice involved. As a result, these IV. Using blood samples from Alzheimer’s patients, Fiala discoveries offer new, promising perspectives for the et al., 2007 have shown that bisdemethoxycurcumin treatment of Alzheimer’s disease. boosts macrophage activity to normal levels, helping to Conclusion clear amyloid beta. They also observed that bisdemethoxycurcumin was more effective in promoting Alzheimer’s disease, which is considered as one of the the clearance of amyloid beta in some patients’ blood curse for mankind, is now become curable at last. than others, hinting at a genetic element. Further study Scientists make it possible by identifying the actual cause revealed the genes involved are MGAT III and Toll-like of the disease. The defective cutting pattern of Beta receptors, which are also responsible for a number of Amyloid Precursor Protein and dysregulation of Tau other key immune functions. Bisdemethoxycurcumin protein are mainly responsible for the disease, although enhances the transcription of these genes, correcting mutations in different genes of chromosome-1, 14, 19, 21 the immune defects seen in Alzheimer’s patients. are also the agents for the disease. The disease can be ROLE OF VITAMINS IN PREVENTING ALZHEIMER’S diagnosed by using different modern techniques like as- DISEASE Eye test, PET scan etc. However, the Alzheimer’s disease Niacin: A study examined whether dietary vitamin B3 can be cured mainly by using different drugs. Among (niacin) could prevent cognitive decline and Alzheimer’s them, the most common is Memantine which is, by its disease, suggests that higher intake of niacin did appear action, a NMDA receptor antagonist. Other drugs like, to be associated with a slower annual rate of cognitive Exelon which acts as a cholinesterase inhibitor are also decline, leading the researchers to conclude that dietary useful. The drug Hydergine also reduce the harmful niacin may actually protect against Alzheimer’s disease. effects of the disease by expressing its medicinal Vitamin E: Scientists has demonstrated that in the animal properties like as increasing blood supply, oxygen and form of the amyloid beta peptide, the antioxidant vitamin level of neurotransmitters in the brain cells and by its E slowed the destruction of brain cells as it appears to in antioxidant properties. Among natural products, the leaf the human form, but the patients may have complain of extract of Ginkgo biloba, is also acts as an important drug nausea, intestinal cramping, fatigue or blurred to prevent the disease by showing its antioxidant and vision(Kappus and Diplock,1992). neuroprotective effects against the plaques. Treatment with vitamins like vitamin E and Niacin is also proved to ROLE OF HORMONES IN PREVENTING be useful. Hormonal treatment with Estrogen shows ALZHEIMER’S DISEASE fruitful result. However, the peoples of Oriental countries Estrogen as alzheimer’s preventer: Animal studies have are less affected by Alzheimer’s than from peoples of shown that administration of estrogen to estrogen- Western countries. This is due to the fact that, peoples deficient laboratory animals restores the number of neural of Oriental countries take turmeric in their daily food, synapses, causes beta-amyloid to be more soluble and which prevents them from all types of Dementia. The has an antioxidant effect. A recent descriptive study medicinal effect of turmeric is to reduce the level by showed a lower relative risk of Alzheimer’s disease and a increasing macrophage activity in brain, by acting as metal later onset of dementia in those who had taken estrogen, chellator, by acting as antioxidant and by other important compared with those who had not. The apparent benefit functions. Recent research have suggests that, sea drug was increased if the length of treatment was more than Bryostatin, which is very useful to treat cancer, can also one year (Goodman et al., 1996). reduce the level of Aâ amyloid plaque formation. Some New cancer drug may help alzhemiers disease : A new drugs like cx516 proved to be useful in mouse model but study shows that the experimental drug BRYOSTATIN are harmful for human body. Other researchers suggest that is proved to be useful in cancer prevention stimulates that, the drug Sodium Phenylbuterate, which is useful in proteins needed to form long-term memories, an ability renal disorder, can help in curing Alzheimer’s disease. It lost in the early stages of Alzheimer’s disease. Researchers has also been found that, peoples who use NSAID (Non found treating sea slugs (Hermissenda mollusks) with Steroidal Anti-inflammatory Drugs) are less affected by the drug-BRYOSTATIN, days before a new learning Alzheimer’s disease. However, studies have shown that activity significantly increased their long-term memory people, who take coffee or tea daily, are also less affected 164 Suman Pratihar et al. /J. Appl. & Nat. Sci. 2 (1): 159-164 (2010) by the disease. A recent study with animal model indicates in a rabbit model of Alzheimer’s disease. The Journal of that caffeine appears to block several of the disruptive Neuroinflammation, vol.5. effects of cholesterol that make the blood-brain barrier Danysz, W. and Parsons, C.G. (2003).The NMDA receptor leaky where blood-brain barrier acts as a filter to protect antagonist memantine as a symptomatological and neuroprotective treatment for Alzheimer’s disease: the brain from potentially harmful chemicals carried in preclinical evidence. International journal of Geriatric the bloodstream(Chen et al.,2008). psychiatry, 18: S23-S32. Recommendations Fiala, M., Liu, P.T., Espinosa-Jeffrey, A., Rosenthal, M.J., Bernard, G., Ringman, J.M., Sayre, J., Zhang, L., Zaghi J., Recommendations for Alzheimer disease apply to Dejbakhsh, S., Chiang, B., Hui, J., Mahanian, M., Baghaee, dementia disorders in general. The recommendations for A., Hong, P. and Cashman, J. (2007). 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Estrogens attenuate and corticosterone exacerbates •Consume a low-fat diet. excitotoxicity, oxidative injury, and amyloid beta-peptide •Eat cold-water fish (like tuna, salmon, and mackerel) rich toxicity in hippocampal neurons. J Neurochem , 66:1836-44. in omega-3 fatty acids, at least 2 to 3 times per week. Hernandez, F. and Avila, J. (2007). Tauopathies. Cell. Mol. •Reduce your intake of linoleic acid found in margarine, Life Sci., 64 (17): 2219–33. butter, and dairy products. Kappus, H. and Diplock, A.T. (1992). Tolerance and safety of •Increase antioxidants like carotenoids, vitamin E, and vitamin E: a toxicological position report. Free Radic BiolMed, vitamin C by eating plenty of darkly colored fruits and 13:55-74. Kemppainen, N.M., Aalto, S. and Karrasch, M., (2008). vegetables. 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